PROJECT SUMMARY The ventricular conduction system (VCS) is a multicellular network comprised of highly specialized cardiomyocytes that orchestrate the near synchronous excitation and contraction of working ventricular myocardium. Purkinje cells (PCs) comprise the most distal portion of the VCS and they have been implicated as arrhythmic triggers in acquired and inherited forms of arrhythmia. However, the underlying molecular mechanisms responsible for PC pro-arrhythmic behavior is incompletely understood, precluding the development of rationally-based therapies for these conditions. Through differential transcriptional profiling of highly enriched populations of cardiac PCs vs. working ventricular myocytes (VMs), our lab identified the dopamine D2 receptor (D2R), a G-protein coupled receptor (GPCR), as being highly enriched in PCs compared to VMs. Based on the established role of this receptor in cellular excitability within the nervous system, we hypothesized that D2R modulates PC electrophysiology and may play a potential role in the arrhythmogenic potential of these cells in the VCS. Using a panel of selective D2R ligands and arrhythmogenic animal models, we are evaluating the role of D2R in PC physiology and disease pathogenesis. These studies could lead to D2R as a novel target to ameliorate PC-dependent arrhythmias.